This invention relates to a process for the selective N-formylation of N-hydroxylamines.
While there are several published methods for the N-formylation of N-hydroxylamines, many of these routes have proven to be problematic. Disproportionation of the hydroxylamine to oximes and formylated primary amines is common, as is the formation of O-formylated and N,O-bis-formylated by-products. Methods which have proven to minimize by-product formation often require extended reaction times and elevated temperatures, which are impractical for large-scale preparations. Thus, there is a continuing need for an efficient method of selectively formylating the nitrogen of an N-hydroxylamine.
The instant invention discloses a large-scale synthesis of N-hydroxyformamides from N-hydroxylamines and 2,2,2-trifluoroethylformate. While the formylation of enolates with 2,2,2-trifluoroethylformate has been disclosed (Zayia, G. H. Organic Lett. 1999, 1, 989-991), the formylation of N-hydroxylamines with this reagent has not previously been described.
The process of the instant invention provides a selective N-formylation of N-hydroxylamines to provide N-hydroxyformamides which minimizes by-product formation.
In one embodiment of the instant invention is provided a process for the conversion of an N-hydroxylamine to an N-hydroxyformamide comprising reacting the N-hydroxylamine with 2,2,2-trifluoroethylformate in an optionally buffered solvent.
The following terms have the meanings specified:
The term xe2x80x9calkyl,xe2x80x9d as used herein, represents a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom.
The term xe2x80x9cC1-C4 alkyl group,xe2x80x9d as used herein, represents a straight or branched chain saturated hydrocarbon radical having from one to four carbon atoms. Alkyl groups of this invention include methyl, ethyl, propyl, tert-butyl, and the like.
The term xe2x80x9caryl,xe2x80x9d as used herein, represents phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, and indenyl. Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring can be attached through either the saturated or unsaturated part of the group.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, represents an aryl group attached to the parent group through an alkyl group.
The term xe2x80x9cbuffered solvent,xe2x80x9d as used herein, represents a solvent containing an agent capable in solution of neutralizing acids and bases and thereby maintaining a pH at or near the original pH of a solution during the course of a reaction. Representative buffering agents carbonate salts such as sodium carbonate, potassium carbonate, calcium carbonate, and the like; bicarbonate salts such as sodium bicarbonate, potassium bicarbonate, and the like; phosphate salts such as potassium phosphate, potassium hydrogenphosphate, sodium dihydrogenphosphate, and the like; tertiary amines such as triethylamine, diisopropylethylamine, and the like; optionally substituted pyridines such as 2,6-lutidine, pyridine, collidine, and the like; imidazole; and carboxylate salts such as sodium formate, potassium carbonate, and the like.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, represents a monovalent saturated cyclic hydrocarbon group.
The term xe2x80x9c(cycloalkyl)alkyl,xe2x80x9d as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an alkylene group.
The term xe2x80x9cxe2x80x94C2-C8 dialkyl ether,xe2x80x9d as used herein, represents xe2x80x94R1xe2x80x94Oxe2x80x94R2, wherein R1 and R2 are independently a C1-C4 alkyl group, or, R1 and R2, together with the oxygen atom to which they are attached, form a tetrahydrofuranyl or tetrahydropyranyl ring.
The term xe2x80x9celectron-withdrawing group,xe2x80x9d as used herein, represents a group which draws electrons to itself more than a hydrogen atom occupying the same position in the molecule would. Examples of electron-withdrawing groups include alkanoyl, arylsulfonyl, alkylsulfonyl, and the like.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, represents a cyclic aromatic group having five or six ring atoms wherein at least one ring atom is selected from the group consisting of oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon. Heteroaryl groups of this invention include those derived from furan, imidazole, isoquinoline, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, quinoline, thiazole, 1,3,4-thiadiazole, thiene, triazole, and tetrazole.
The term xe2x80x9cheteroarylalkyl,xe2x80x9d as used herein, represents a heteroaryl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9cN-hydroxylamine,xe2x80x9d as used herein, represents NHR3(OR4), wherein R3 is any group considered by those skilled in the art to be stable under the reaction conditions; and R4 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heteroaryl, and heteroarylalkyl.
The term xe2x80x9cN-hydroxyformamide,xe2x80x9d as used herein, represents NR3(CHO)(OR4), wherein R3 and R4 have been previously defined.
The term xe2x80x9csubstituted pyridine,xe2x80x9d as used herein, represents a pyridine optionally substituted with one, two, or three methyl groups. Examples of substituted pyridines include 2-picoline; 3-picoline; 4-picoline; 2,6-lutidine; 2,5-lutidine; 2,4-lutidine; 2,4,6-collidine; 2,3,5-collidine; and the like.
The compounds and process of the instant invention will be better understood in connection with the following synthetic scheme which illustrates the method by which the compounds of the instant invention are prepared. 
As shown in Scheme 1, compounds of formula (1) can be converted to compounds of formula (3) by treatment with 2,2,2-trifluoroethyl formate (2), which can be prepared according to the procedure described in J. Chem. Soc. B 1971, 826-831. Examples of solvents used in these reactions include tetrahydrofuran, methyl tert-butyl ether, diethyl ether, ethyl acetate, isopropyl acetate, 2,2,2-trifluorethanol, formic acid, toluene, and mixtures thereof. The reaction temperature is about 35xc2x0 C. to about 75xc2x0 C. and depends on the solvent chosen. Reaction times are typically about 4 to about 18 hours. When the compounds of formula (1) or the compounds of formula (3) are acid-sensitive, the reaction is preferably buffered. Representative buffering agents include carbonate salts, bicarbonate salts, phosphate salts, tertiary amines, optionally substituted pyridines, imidazole, and carboxylate salts. Preferably, the buffer is either imidazole or a carboxylate salt. More preferably, the buffer is either imidazole or sodium formate.